4. Green Manufacturing Problems For Pharmaceutical Manufacture 27 January 2010

5. Background The funds committed by GSK and EDB towards green manufacturing (~33 million) will be used to fund green manufacturing research Through the completion of research and development projects applied to sustainable manufacturing problems, we will increase the green manufacturing skill set in Singapore. The program will last approximately 10 total years GSK’s role is to serve as strong industrial sponsors, partnering with EDB to ensure goals of funding are met –Supply industry problems –Organize RFPs and assist in review of proposals –Provide contacts to assist principal investigators – guidance on problems, potentially materials, exposure of trainees to industry

6. Timeline and Process – Year 1

7. Proposal Review Criteria Alignment with the strategic objectives of the Fund –Strengthening the capability and training a talent pool in Singapore to meet the sustainable manufacturing challenges that local industries will face –Further enhance the working relationship between universities, institutes and local companies through interdisciplinary research into sustainability –Enabling Singapore to become a leader in sustainability research for pharmaceuticals and fine chemicals. Impact of the proposal to sustainable manufacturing science Potential for eventual industrialization of research outputs Originality / Novelty of Proposal

8. The Problems 27 January 2010

9. Improving Manufacturing Sustainability: An Overview IN (kg) Product PROCESS Raw Material 1 Raw Material 5 Raw Material 2 Raw Material 4 Raw Material 3 Out (kg) LOSSES Waste Reject By-products Re-cycleRe-use Down-cycleRe-sale £ ££ Pharmaceutical manufacture typically has > 100 kg raw material consumption/kg product Disposal costs Infrastructure costs Energy costs

10. Improving Manufacturing Sustainability: An Overview (2) Basic principles of Green Manufacturing Maximize resource efficiency (i.e., energy and mass) Eliminate and minimize EHS hazards Design systems using life cycle analysis thinking Problem Statement Emphasis

11. Breakdown of Sustainable Manufacturing Areas of Focus Sustainable Manufacturing Problem Areas –Chemical Transformations –Biotransformations –Physical Transformations –Solvent Selection and Optimization –Unit Operation Selection and Optimization –Equipment and Technology Selection –Controls Selection and Optimization –Recovery and Reuse Integration –Waste Treatment and Minimization –Lifecycle Analysis –Facilities and Supply Chain 1 st RFP, 27 January 2010 GSK staff have prepared problem statements under each of these problem areas. These problem statements are a ‘snapshot’ and will continue to be developed for future proposal calls

12. Chemical and Bio Transformations Key green chemistry research areas - a perspective from pharmaceutical manufacturers –David J. C. Constable a, Peter J. Dunn* b, John D. Hayler c, Guy R. Humphrey d, Johnnie L. Leazer, Jr. d, Russell J. Linderman e, Kurt Lorenz f, Julie Manley g, Bruce A. Pearlman h, Andrew Wells i, Aleksey Zaks h and Tony Y. Zhang f –Green Chemistry, Issue 7, No. 5, pg 411 Commonly used reactions which need improvements Aspirational Reactions - not commonly used, need solutions Amide formation avoiding poor atom economy reagents C–H activation of aromatics (cross coupling reactions avoiding the preparation of haloaromatics) OH activation for nucleophilic substitutionAldehyde or ketone + NH3 + X to give chiral amine Reduction of amides without hydride reagents Asymmetric hydrogenation of unfunctionalised olefins/enamines/imines Oxidation/Epoxidation methods without the use of chlorinated solvents New greener fluorination methods Safer and more environmentally friendly Mitsunobu reactions N-Centred chemistry avoiding azides, hydrazine etc

13. Chemical and Bio Transformations (2) Some specific biotransformation challenges Ester to amide conversion Nitrile to primary amine Chiral epoxidation of alkenes N-alkylation via activated alcohol Mitsunobo Reaction Hydride Reduction OH activation

14. Physical Transformations J. Am. Chem. Soc., 2003, 125 (28), pp 8456–8457 Problem 1 - Dematerialization 1.The manufacture of active ingredients typically represents > 70% of the total carbon footprint of an oral tablet 2.If through enhanced exposure the amount of active ingredient could be reduced, the reduction in total carbon footprint would be nearly proportional 3.Bioenhancement or targeted deliver can help accomplish this objective Problem 2: Improve energy efficiency of particle forming and formulation operations 1.Energy efficient mfg. methods are desired to produce medicines 2.Ways of minimizing the energy of key unit operations (crystallization, particle size reduction, granulation, drying) are desired (e.g., what is optimum particle fomation and formulation method from an energy/mass perspective? Bend Research Web Site

15. Facilities and Supply Chain Problem 1: Greener facilities Only 10-30% of the total energy associated with a facility ends up going into a product Function of –facility design –energy use option What does facility of the future look like? Problem 2: Global Supply Chains Active ingredients and tablets are often shipped to several countries for manufacture / packaging prior to getting to patients What is the total carbon footprint of the supply chain in relation to manufacturing processes? What is the time impact? Full complexity? Needed: optimization of current pharma supply chains

16. Solvent Selection and Optimization Problem 1: Intelligent solvent selection with sustainability as objective 1.Commonly used solvents are still mostly petroleum derived 2.Heavy use of chlorinated solvents 3.Solvent selection performed through screening rather than prediction 4.Little use of alternative solvents (e.g., ionic solvents) 5.Need acceptable halogen replacements, knowledge of when ionics make sense, intelligent selection of solvents to meet sustainability needs Problem 2: Dipolar Aprotic Replacements 1.Dipolar aprotic solvents synthetically useful 2.Most dipolar aprotics teratogenic (or exhibit another type of toxicity) 3.Not always readily recoverable – high boiling, water miscible 4.Substitutes needed

17. Unit Operation Selection and Optimization The most energy intensive unit operations in pharmaceutical manufacturing are distillation and drying Inerting is one of the most frequent unit operations used, and contributes significantly to VoC emission to atmosphere Crystallization is a critical unit operation to control and deliver the correct physical attributes for active ingredients Catalysts are frequently homogeneous and are almost always used only once and disposed of Needs 1. Energy efficient alternatives to distillation for removal of solvent from product or transfer of product from one solvent phase to another 2. Process intensification of drying to reduce energy input 3. Method for separating trace organics from high volume nitrogen streams without using activated carbon or extreme low temperatures 4. Evaluation of methods for immobilizing frequently used homogeneous catalysts; learnings from bulk chemical catalysis that can be applied to pharmaceutical mfg

18. Lifecycle Analysis Blister Pack Problem Many tablets are packaged using blister packs which are constructed of aluminum and polyvinyl chloride The blister pack is not made from a sustainable source, and adds an additional carbon burden to our products Are there alternative but equally performing materials which have a better ecological profile? Inhaled Device Problem Products like Advair for asthma or other respiratory conditions, often use complex devices to deliver microgram quantity doses Each device is typically disposed of after use What is the footprint of the device versus the drug? Can a device be made that is inherently recycleable while meeting patient safety requirements?

19. Equipment and Technology Most pharmaceutical processing is performed in batch reactors Batch reactors can be limiting for chemical transformations –Highly exothermic reactions may be unsafe –A relatively high amount of solvent is required simply to agitate the contents sufficiently –Selectivity suffers from long quench times /cooling rates Needs What can continuous reaction modes offer pharmaceutical manufacture? New chemistry? Improved volumetric efficiency of known chemistry? Improved selectivity of known chemistry? What is the true cost savings of having a continuous process

20. Controls Selection and Optimization Most pharmaceutical manufacturing control schemes are ‘simple’ with a high manual component –Control of key attributes (e.g., purity) through sampling, offline analysis, report back result, manually move control system to next step in recipe –This results in processes with significant wait and hold periods, which consumes facility time and thus energy –In addition, real-time alerts to operations staff not available As a result of US FDA’s Quality by Design and Process Analytical Technologies Initiatives, companies have invested heavily in on-line instrumentation –Benefits have yet to be fully realized Needs 1. Advanced control algorithms for common industry control tasks which can pass regulatory scrutiny (e.g., fully validated) Drying endpoint Distillation endpoint Reaction endpoint Crystallization 2. Data reduction techniques that address common sources of noise for instruments

21. Recovery and Reuse Integration Solvents consist of 85% of the mass used in active ingredient manufacture Pharmaceuticals recycle less streams / solvents back to processes than other industries (e.g., bulk chemicals or petrochemicals) Causes –Production volumes generally low, wide variety of products; recovery cost can often be high –Regulatory and product purity concerns associated with recycle Needs 1. Assessment of solvent recovery economics for an industrial cluster versus an individual mfg site 2. Energy efficient alternatives to thermal methods for solvent recovery 3. Assessment of stream recycle economics for our industry

22. Waste Treatment and Minimization Pharmaceuticals have relatively small volume individual waste streams which are often too concentrated (e.g., high COD) to treat biologically but too dilute to incinerate cost effectively Many of our compounds are environmentally refractory- v. slow degradation in the environment Common solvents in aqueous wastes include simple alcohols and ketones In addition to organics, pharmaceutical wastes often have high inorganic loads Needs Evaluation of treatment alternatives for high COD waste streams – what is best from a sustainability perspective (e.g., concentration and burning, dilution and biotreatment, etc..) Separation solutions (e.g., membranes) for ketone and alcohol laden wastes for either solvent removal or waste concentration Common solvents in aqueous wastes include simple alcohols and ketones Integrated, efficient treatment solutions for high inorganic, high organic wastes

23. Summary An example of common pharmaceutical problems has been provided. The first RFP will be for chemical, bio, and physical transformations There are many more problems! This list will change. We are open to additional views Many solutions will likely benefit from multidisciplinary research, e.g. –Can a continuous reactor affect the way a transformation is discovered? –How are solvents selected to meet both an ecological and synthetic objective? –How do bio-enhanced formulations perform in animal models? We look forward to collaborating with you and to your contribution in making Singapore a leader in green manufacturing

24. Close Please contact us should you have any questions or problems during the proposal process AND We ask for your cooperation and patience. This effort is one of the first of its kind for GSK. We are learning….

25. Submission Both soft copy and hard copy of the proposal are required. Send soft copy to: GSK-EDB-GSM@gsk.com Send hard copy to: Timeline :before 15 March 2010 Ye Weiping GSK-Singapore Sustainability Partnership Technical Development GlaxoSmithKline 1 Pioneer Sector 1 Singapore 628413

26. Do more, feel better, live longer